Caffeine Pharmacology

Description: Caffeine is a naturally occurring xanthine derivative
used as a CNS and respiratory stimulant, or as a mild diuretic. Other xanthine
derivatives include the bronchodilator theophylline and theobromine, a compound
found in cocoa and chocolate. Caffeine is found in many beverages and soft
drinks. Caffeine is often combined with analgesics or with ergot alkaloids
for the treatment of migraine and other types of headache. Caffeine is also
sold without a prescription in products marketed to treat drowsiness, or
in products for mild water-weight gain. Caffeine was first approved by the
FDA for use in a drug product in 1938. Clinically, it is used both orally
and parenterally as a respiratory stimulant in neonates with apnea of
prematurity. Caffeine reduces the frequency of apneic episodes by 30-50%
within 24 hours of administration.[2070] Caffeine is preferred over theophylline
in neonates due to the ease of once per day administration, reliable oral
absorption, and a wide therapeutic window. A commercial preparation of parenteral
caffeine, Cafcit®, was FDA approved for the treatment of apnea of prematurity
in October 1999, after years of availability only under orphan drug status
(e.g., Neocaf®). The FDA has continued the orphan drug status of the
approved prescription formulation.

Mechanism of Action: Caffeine is a mild, direct stimulant at all levels
of the CNS and also stimulates the heart and cardiovascular system. The related
xanthine, theophylline, shares these properties and is widely used in the
treatment of pulmonary disease. Both caffeine and theophylline are CNS
stimulants, with theophylline exerting more dramatic effects than caffeine
at higher concentrations. Caffeine also stimulates the medullary respiratory
center and relaxes bronchial smooth muscle. Caffeine stimulates voluntary
muscle and gastric acid secretion, increases renal blood flow, and is a mild
diuretic.

While the clinical responses to caffeine are well known, the cellular mechanism
of action is uncertain. Several theories have been proposed. At high
concentrations, caffeine interferes with the uptake and storage of calcium
by sarcoplasmic reticulum of striated muscle. While this action would explain
the effects of caffeine on cardiac and skeletal muscle, it does not appear
to occur at clinically achievable concentrations. Inhibition of
phosphodiesterases (and subsequent accumulation of cyclic nucleotides) also
does not appear to occur at clinically achievable concentrations.

Currently, it is believed that xanthines act as adenosine-receptor antagonists.
Adenosine acts as an autocoid, and virtually every cell contains adenosine
receptors within the plasma membrane. Adenosine exerts complex actions. It
inhibits the release of neurotransmitters from presynaptic sites but works
in concert with norepinephrine or angiotensin to augment their actions.
Antagonism of adenosine receptors by caffeine would appear to promote
neurotransmitter release, thus explaining the stimulatory effects of caffeine.
Recently, a distinct syndrome has been associated with caffeine withdrawal.
It is possible that the manifestations of caffeine withdrawal may be secondary
to catecholamine or neurotransmitter depletion.

The following mechanisms of action are hypothesized for caffeine's action
in apnea of prematurity:

Stimulation of the respiratory center,

Increased minute ventilation,

Decreased threshold to hypercapnia,

Increased response to hypercapnia,

Increased skeletal muscle tone,

Decreased diaphragmatic fatigue,

Increased metabolic rate, and

Increased oxygen consumption.

All of these actions are thought to be related to adenosine receptor antagonism.

Pharmacokinetics: Caffeine is administered orally and intravenously.
Caffeine and citrated caffeine are well absorbed from the GI tract. Absorption
from suppositories may be slow and erratic. Following oral administration,
peak plasma concentrations in adults are reached within 50-75 minutes.
Therapeutic caffeine concentrations are reported to be 5-25 mg/L in adults.
Caffeine is distributed rapidly to all body tissues and readily crosses the
blood-brain and placental barriers. It is distributed into breast milk. Caffeine
is roughly 36% bound to plasma proteins.

In adults, caffeine is partially metabolized in the liver via demethylation
reactions dependent on the CYP-450 1A2 isoenzyme; major metabolites include
paraxanthine (80%), theobromine (10%) and theophylline (4%). The plasma half-life
of caffeine is 3-7 hours in adults.

*Special populations: Caffeine is administered orally and intravenously.
Caffeine and citrated caffeine are well absorbed from the GI tract in neonates.
In neonates, the oral administration of caffeine results in peak concentrations
in 0.5-2 hours. Formula feedings do not affect the time to maximum concentrations
after oral dosing. Therapeutic plasma concentrations of caffeine for the
treatment of neonatal apnea of prematurity are roughly 13-25 mg/L, however,
concentrations of 26-40 mg/L may be needed for some infants to obtain a reduction
in apneic episodes.[2070]

Caffeine metabolism in neonates is limited due to their immature hepatic
enzyme systems. In neonates, it is interesting to note that interconversion
from theophylline to caffeine has been noted. Unchanged caffeine and its
metabolites are excreted in the urine. Plasma half-life for neonates may
vary widely, from 65-100 hours, and the fraction of caffeine excreted unchanged
in the urine is roughly 86% within 6 days. Young infants have a plasma half-life
of caffeine of 3-4 days. By 9 months of age post-term, the plasma half-life
and urinary excretion of unchanged caffeine in infants approximates that
of adults (1%). Cytochrome P450 metabolism of caffeine is inhibited in infants
who are breast-fed; formula feeding does not appear to affect the
pharmacokinetics of caffeine in infants. The pharmacokinetics of caffeine
have not been studied in neonates with impaired renal or hepatic function;
however, caffeine elimination is more dependent on renal clearance in premature
neonates and neonates than in older infants or adults, due to the underdeveloped
hepatic metabolism and renal elimination. If renal or hepatic impairment
is present, caffeine elimination may be reduced, and serum concentrations
should be carefully monitored and dosages adjusted to avoid toxicity. Serious
toxicity has been reported in infants with serum caffeine concentrations
> 50 mg/L.

Adverse Reactions

Caffeine is a CNS stimulant. Many adverse reactions to caffeine are an extension
of caffeine's pharmacologic actions. At therapeutic or nontoxic doses, caffeine
can cause tremor, sinus tachycardia, and heightened attentiveness. Other
adverse reactions include diarrhea, excitement, irritability, insomnia, headache,
muscle twitches and palpitations. Alterations in blood glucose, such as
hyperglycemia or hypoglycemia, have been reported. After excessive doses,
caffeine can cause considerable nausea/vomiting and anxiety. Cardiac arrhythmias,
seizures, and delirium are possible after deliberate overdoses. In humans,
a caffeine level of > 50 mg/L may produce toxic symptoms.

Caffeine is a mild diuretic. Polyuria can occur. Increased creatinine clearance
and increased urinary calcium (hypercalciuria) and sodium excretion are reported
in the literature.

In controlled clinical trials of caffeine citrate injection in premature
neonates, the following adverse events occurred more commonly in
caffeine-treatment groups than with placebo: accidental injury, bleeding,
cerebral hemorrhage, disseminated intravascular coagulation, dyspnea, pulmonary
edema, metabolic acidosis, xerosis, rash (unspecified), renal failure
(unspecified), retinopathy of prematurity, and skin breakdown. In neonates,
intolerance or overdose of caffeine may manifest as tachypnea, hyperglycemia,
azotemia, fever, or seizures. No deaths have been reported in relation to
overdose of caffeine in neonates. During controlled clinical trials of caffeine
citrate in premature infants, necrotizing enterocolitis was reported in 6
patients, 5 of whom were administered caffeine. Three of the infants died.
The incidence was 4.3% in caffeine-treatment groups vs. 2.6% of placebo-treated
infants. Feeding intolerance (3.5%), gastritis (2.2%) and gastrointestinal
bleeding (2.2%) also occurred in the caffeine treatment groups. Clinicians
should be alert for signs and symptoms of gastric distress, abdominal bloating,
nausea, vomiting, bloody stools and lethargy in treated infants.

High caffeine intake has been reported to cause spermatogenesis inhibition
in male animals, as noted by spermatogenic cell degeneration within the testes.
Although controversial, infertility, as manifested by increased difficulty
in getting pregnant, has been reported in females. Couples who are pursuing
pregnancy should probably limit excessive intake of caffeine.

In 1992, a distinct caffeine withdrawal syndrome was described. Patients
who consume or receive caffeine daily for several weeks experience notable
physical and psychiatric responses including lethargy, anxiety, dizziness,
or headache upon caffeine withdrawal.

Contraindications/Precautions

The OTC use of caffeine products is not recommended in children under the
age of 12 years.

Caffeine with sodium benzoate injection (see Separate monograph) is not
recommended for use in premature neonates because the benzoate may displace
bilirubin and induce kernicterus. In addition, elevated serum concentrations
of benzoate, similar to benzyl alcohol, have been associated with neurological
disturbances, hypotension, gasping respiration, and metabolic acidosis (i.e.,
'gasping syndrome') in neonates. Make sure to use Cafcit??, which does not
contain sodium benzoate, or to use an extemporaneously compounded caffeine
citrate injection in newborns and premature infants. The safety and efficacy
of the prescription used of caffeine in infants for longer than 12 days has
not been established. Caffeine has not been established for the prophylaxis
of sudden infant death syndrome (SIDS) or for use prior to extubation in
mechanically ventilated infants.

Caffeine is a central nervous system stimulant. Caffeine should be used
cautiously in patients with anxiety disorders and/or panic disorder because
it can aggravate these conditions. Patients suffering from insomnia should
not consume caffeine, nor should caffeine be consumed prior to retiring because
it can cause insomnia. In overdoses, caffeine has been associated with seizures
and it should be prescribed cautiously to those patients with a seizure disorder.

Caffeine should be used cautiously in those patients, including neonates,
with cardiac disease. Caffeine can stimulate the force of contraction and
can increase heart rate. It may increase left ventricular output and stroke
volume. Patients who have angina or a history of cardiac arrhythmias should
not receive or should minimize their intake of caffeine. Caffeine should
not be taken in the first few days-weeks after a myocardial infarction. Patients
with hypertension should minimize their intake of caffeine.

Caffeine should be used cautiously in those with hepatic disease or hepatic
impairment. Caffeine clearance may be delayed, leading to toxicity. Also,
renal impairment or renal failure may delay caffeine clearance. It should
be noted that caffeine elimination is more dependent on renal clearance in
neonatal prematurity and term neonates than in older infants or adults, due
to the underdeveloped hepatic metabolism and renal elimination of drugs in
general. Thus monitoring of serum caffeine levels is recommended in neonates
or neonatal prematurity, especially those with renal or hepatic impairment.

Patients with diabetes mellitus should not receive or should minimize their
intake of caffeine. Although the effects are mild, caffeine can either raise
or decrease blood sugar. In neonates, both hypoglycemia and hyperglycemia
have been observed.

Patients with thyroid disease, especially hyperthyroidism, should not receive
or should minimize their intake of caffeine. The stimulatory effects of caffeine
can be augmented in hyperthyroidism.

Caffeine can stimulate gastric secretions. Patients with peptic ulcer disease
should minimize their intake of caffeine because the condition can be aggravated.
In neonates, there are reports in the literature suggesting a possible
association between the use of methylxanthines like caffeine and the development
of necrotizing entero-colitis. Six cases of this disease were reported during
clinical trials of caffeine injection. All preterm neonates treated with
caffeine should be monitored for the development of gastric side-effects
(i.e., abdominal distension, vomiting, bloody stools, and lethargy).

Caffeine is generally classified in FDA pregnancy risk category B; however,
Cafcit?? (injectable and oral solution) prescription products are classified
in FDA pregnancy risk category C but concern for teratogenicity of caffeine
is not relevant when such products are administered for neonatal apnea.

Caffeine easily crosses the placenta; fetal blood and tissue concentrations
approximate maternal concentrations. There are no large, well-controlled
studies of caffeine administration in pregnant women; it is generally recommended
that the intake of caffeine-containing beverages, like coffee, teas, and
sodas, be limited in pregnancy (usually no more than 1-2 caffeine-containing
beverages/day) or avoided if possible. Likewise, caffeine-containing medications
should be limited to use only when absolutely necessary. Low to moderate
caffeine intake does not appear to increase the risk of congenital malformation,
spontaneous abortion, pre-term birth or low birth weight. The association
between high daily intake (> 500 mg/day) of caffeine and increased rates
of low birth weight, spontaneous abortion, difficulty in getting pregnant
or infertility is still controversial, as some studies have not controlled
for concomitant cigarette smoking. There are no adequate and well-controlled
studies of caffeine administration in pregnant women. Neonatal arrhythmias
(e.g., tachycardia, premature atrial contractions) and tachypnea have been
reported when caffeine was consumed during pregnancy in amounts > 500
mg/day; caffeine withdrawal after birth may account for these symptoms.

Cytochrome P450 metabolism of caffeine is inhibited in infants who are
breast-fed; formula feeding does not appear to affect the pharmacokinetics
of caffeine in infants. Peak caffeine milk levels usually occur within 1
hour after the maternal ingestion of a caffeinated beverage; with milk:plasma
ratios of 0.5-0.7 reported. Although only small amounts are secreted in
breast-milk, caffeine can accumulate in the neonate if maternal ingestion
is moderate to high. Higher caffeine intake (> 500 mg/day) by a nursing
mother may cause irritability or poor sleeping patterns in the infant who
is breast-feeding. Although the American Academy of Pediatrics generally
considers the usual use of caffeinated beverages to be compatible with lactation,
nursing mothers should limit their intake of beverages containing caffeine
if possible. Caffeine containing drug-products should be used cautiously
during lactation due to their high caffeine contents.

Mothers who are breast-feeding infants who are prescribed caffeine for apnea
should avoid additional caffeine.

Tobacco smoking (cigarettes) has been shown to
increase the clearance of caffeine. Also, passive smoke exposure may cause
an increase in caffeine clearance. This may help to explain why tobacco smokers
often have concommitantly high caffeine intakes. Tobacco smoke contains
hydrocarbons that induce hepatic CYP450 microsomal enzymes. Because the effect
on hepatic microsomal enzymes is not related to the
nicotine component of tobacco, sudden smoking
cessation may result in a reduced clearance of caffeine, despite the initiation
of nicotine replacement. Caffeine dosage may need to be reduced at the cessation
of smoking.

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